Marc E. Agronin, MD

To wrap up my final question, how will the future of our field look with increasing early diagnosis of Alzheimer's? Now that we have targeted therapies to you know change trajectory, potentially disease-modifying. Yes, no – Again, we can fight about the data. We're not going to talk about the data today, we've talked about that a lot in other things, and other sessions, and there's lots of data out there. How do you think our field is truly going to change with an emphasis on early diagnosis? Is this feasible? You and I have had more calls in the last 3 days. Speaking myself, in the last 3 days, I've had more calls and emails than I've had in the last, I would say, almost a year? I don't know. Six months easily combined in literally the first 3 days since approval. How is this going to change? Are we going to be screening people more like really this time? Are we going to be bringing people earlier? Are people going to understand what MCI [mild cognitive impairment] is? Our primary care doctor is going to be able to make these types of very challenging decisions. I have a waitlist. I'm not sure if you have a waitlist. I bet you do. What's the future going to be like? What are the next 3, 6, 9, 12 months and 2 years going to look like? 

Well, my hope and this is longer than 3, 6, 9 months since I'm thinking 10, 15 years from now. I would use the model of colonoscopies. I think everyone in their 50s is going to have a multi-level screening. It's going to involve blood tests for amyloid and tau, to begin with. It will involve probably computerized cognitive testing, similar to a lot of what you do in your prevention clinic because you're trying to detect early. You'll have a battery of tests, a little more complicated than a colonoscopy, but maybe a little simpler in other respects. 

That's going to give you an increasing risk, an indication whether this is really Alzheimer's and we will do that to the end of getting you on preventative treatment, and not just lifestyle issues which you've done a lot of work in which is really critically important. Everyone should be focusing on healthy lifestyle, but some sort of specific whether it's immunotherapy or some of these other emerging treatments that you will begin before you become symptomatic. Maybe not 10 or 15 years, it may be a little longer than that, but I envision that's what's going to be the future to actually eradicate this disorder, because you're going to have to start in your 50s. If you wait longer than that, it's going to be a little too late. It’s my guess. Now, that will be for Alzheimer's disease, we have to remember that we still have other forms of neurocognitive disorders like Lewy body disease which are in many ways’ tougher diseases. We have to make sure we keep our focus on those as well, because those are equally as devastating to people and their loved ones. 

 I had a patient today came to me for a prevention, or risk reduction, or learning more about what he could do for modifiable Alzheimer's, and I got the pathology report of his father and he had Lewy body. I said, "Oh, well did he have funny dreams? Oh, yes, he acted out his dreams. He would kick and punch in his sleep. Oh, yes, we'd see these little animals and things like that. That was just Alzheimer's, right?” No, that was Lewy body. Lewy body prevention and treatment are the next frontier and subdividing. Now, that we're going to have these biomarkers is there to, so I completely agree. 

Well, Dr Marc Agronin, this has been a long time coming. We're talking about a new FDA-approved drug. For all the good, for all the bad, for all the controversy, it's here. As physicians that care about our patients and want to help them, we have to figure out some way to help them to balance the risks the benefits, and of course, the costs which we talked a little bit about today. I think our jobs just got a lot harder. 

 As long as it leads to better patient outcomes, it's great but I guess that we'll have to figure that out as things come in and who at what stage, at what dose. We'll hopefully know a lot more, hopefully, we can continue the conversation, and have a similar conversation again. 

 It's true. It's just as you said, it's here, whether clinicians agree, disagree are skeptical, hopeful, it makes no difference. It's here, and we all have the obligation to get on board and get involved with our patients and do what's going to be in their best interest. It's going to be a work in progress but we can't shy away from that. 

 They're going to come to us with questions and that's why you have to give our best opinion. Thanks so much for watching this 

. If you enjoy this content, please subscribe to our e-newsletters to receive upcoming programs and other great content in your inbox. Dr Agronin, thanks so much. 

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Drs Richard S. Isaacson and Marc E. Agronin look to the future of treating Alzheimer disease with the emphasis on early diagnosis. 

Future of Treating Alzheimer Disease 

I just wanted to wrap up on a couple of things. First, blood-based biomarkers. Where's our field going? I think and I hope that our field is going towards blood-based biomarkers, PET [positron emission tomography] scans, expensive and cumbersome radiation. Then we have spinal taps. I like spinal taps to get amyloid and tau. It's reliable. I've been used to it. Patients don't want spinal taps, it's cumbersome, takes a lot of time. Serum biomarkers, the first commercially available amyloid blood biomarker test is available now, I think in most states but not every state. Tau test, P-tau217, for example, are really interesting and compelling data as a biomarker. Whether or not these are used for 1-time diagnostic slices to predict or correlate with positivity of an amyloid or tau scan and that is used for it helping with diagnosis or stratifying with who should get a PET scan or whatever else, or whether it's used to maybe track people over time and wouldn't it be great to have it just like we do HDL [high-density lipoproteins] cholesterol, and LDL [low-density lipoproteins], and total cholesterol in a year and a half, 2 years we’re going to be every 6 months getting amyloid and tau. Also, maybe monitoring trajectory that way? “Oh, they have amyloid but no tau. Oh, maybe they're really early, maybe we need to intervene with the anti-amyloid drug.”

These are all hypothetical things. They sound good, they sound exciting, I'd love to track my patient’s amyloid every 6 months over time, and I want to do that and maybe even plan on doing it, but how realistic is this? When are serum biomarkers, even though they're available, they're going to be available more, how much do we know, and don't know, and what can we expect about serum biomarkers? 

There's a lot of work that needs to be done here. We need to be very cautious that we're not basing diagnoses on these results. There's no question within the next 5 years that we will have relatively accurate ways through just a blood test to detect the presence of amyloid and tau. The question again, is what does that really mean? Does that mean they have Alzheimer's disease? What about someone who has tau but not amyloid or vice versa? Or what about as we're seeing clinical trials where you have a positive tau blood test and you have a negative tau scan? We know this is a heterogeneous disorder, there's different subtypes, depending on where you have deposition in the brain is going to determine to some extent the course for some individuals. 

You can have Alzheimer's disease, at the same time if you have Lewy bodies in the brain. The complexity here is great, and the more you reduce it to single tests, to some extent, you really risk going down the wrong course. I give this example, no one will go to a doctor on a single blood test want them to say, "Yes, you have this cancer or no, you don't". There are other clinical correlates that you have to mix in with this. As the severity of the diagnosis is a life-changing diagnosis, these tests are not like getting to check your cholesterol level or indicating you're a little anemic or not. This is a life-changing diagnosis, and so we owe our patients, their families and loved ones, and we ourselves as clinicians to be careful, cautious, and to be comprehensive. That's the strength of memory disorder centers of the center you have where we put the whole puzzle together. We're not looking at 1 single data point but everything in aggregate and trying to assign something. I would hope that this is going to continue to be the approach and that requires a lot of education and specialists as well. 

I'm really glad you said that. I just want to repeat that for a second, because I get excited about things. I like thinking about the future. I like figuring, “OK, where are we going to be in 5 or 10 years?’ I'm going to try to do that now or yesterday, right? I can't wait till the amyloid blood test come out, but I just want to reiterate what you said. Currently, in medicine, we've come pretty far in certain areas and we would never make a diagnosis of cancer, almost never basically on 1 test, right?

We confirm it, we get corollary, we do that, we repeat it we, so I completely agree. I'm excited about the promise of blood-based biomarkers but we have to be careful. It has to be in the right clinical picture, progressive short-term memory loss, family history of Alzheimer's, to e4 variants. Then the amyloid test in the blood is sky-high. It's probably Alzheimer's disease but I completely agree with you. The panel of tests, the other additional markers, and confirmatory tests, especially if someone's going to be going in a clinical trial, I think it's really important.

The use of blood-based biomarkers for diagnosis of Alzheimer disease in the context of the comprehensive diagnosis. 

Blood-Based Biomarkers for Diagnosis of Alzheimer Disease 

We've talked a lot about aducanumab. What does this do for the rest of the field? How does this impact the treatment landscape of Alzheimer's disease and what about all these other drugs in development? We talked about lecanemab, which is being studied for both early Alzheimer's disease, dementia, mild cognitive, and impairment being studied in large phase 3 studies. We have a galantamine, for example, that's a recent made a big splash a few months ago. Donanemab showed some interesting results too. Fast forwarding, after that 

] paper, there is going to be phase 3 study launching all over now. Here we go again, another antibody has potential, it failed in 1 way but maybe positive in other patients and other subgroups? How do you think this approval affects those studies which you mentioned before where people may not want to enroll? Do you think that increases the likelihood of success that the FDA will look at these data and say, "We don't need a cognitive measure because, on label, there's no cognitive anything in the label for aducanumab. It's a biomarker-based disease". Do you think these additional anti-amyloid agents are going to have a higher likelihood of success based on the precedent that the FDA has now seen? 

Yes, and I would throw into the mix anti-tau treatments also that are being looked at. Yes, so this is 1 question that's been raised is, given the FDA's approach here, is this going to set a precedent for the change the bar in terms of other treatments? I've been to some FDA review committees and it's a tough environment for any treatment for Alzheimer's disease. Almost everything has failed through it and with good reason, either the data is there or it's not there. We need data and we need studies. If someone is presented with a 2-year on average, placebo-controlled trial of some other immunotherapy or any other Alzheimer's treatment. I would add to that that the screening process is very rigorous. I have some studies where it's a 2 or 3-month process of multiple scans, multiple scales, and someone is asking themselves, "Am I going to go through that process for 2 years that to be on potential placebo? I can walk down the street and get this infusion.”

It's going to be an issue and so one question I raise is do we need to change the scope of some clinical trials? Do they need to be shorter? Do they need to get into more quickly open-label? Do we need to make aducanumab a comparator? I don't have answers to these questions, but there's no question as a researcher, and I'm certain any company working on clinical trials, any researcher trying to generate a clinical trial is going to have to think about this in terms of what they're competing with. I'm concerned about its impact on research. I know a lot of people are. Again, it's an issue that is yet to be determined. My sense is, I'm trying to be very optimistic here, is that I think this is going to be a very gradual rollout. I think what we're going to see both from clinicians and payers, is that there's going to be a pretty high bar to qualify for the treatment to get payment for it. Sure, some people are going to walk in and just want to pay cash for this. I don't think that's going to be the majority. I think that will be few and far between, so I think it's going to be done in a very measured way. At least, I hope it is, and this is part of the reason we're talking about this because I think you know these questions really have to be vetted and discussed on every level. There is some consensus because we've seen some of the controversy, we've seen some of the concerns raised amongst colleagues. I think in general, it's better when people are on the same page when we agree on what the best approach is. We want consensus at the end of the day.  

Yep, I agree, and I completely agree with all of your points. Patients do what they want to do and it even opens up the door to what if someone is on aducanumab, they're in another clinical trial and it could be mixing so there's lots of potential issues there that we need to have very frank conversations with patients about. I think that happening is going to be very few and far between, at least I hope it would be. However, there's actually studies being planned for that now. Obviously, if you're on an anti-amyloid drug in a clinical trial, you really should not be on the anti-amyloid drug in practice, that’s easy. But what about an anti-tau drug in clinical trial, but being on the amyloid drug in front? That probably mixes things up and confuses things, but, for example, there's a phase 3 study. It's going to enroll over 3,700 people with semaglutide.

Semaglutide is a GLP-1 drug. It's basically a diabetes drug that's been studied and has some interesting outcomes with cognition and Alzheimer's disease. Basically, they're going to be evaluating whether semaglutide for a 2-year trial, can slow Alzheimer's progression, and actually improve cognitive function. That study to my understanding, I think I probably need to double-check this, but it allows someone to be an anti-amyloid drug. There may be some studies that people could go into and participate in as well as being on aducanumab. How do you track that? How do you analyze for that? Obviously, it's a randomized trial so hopefully, some of that will shake out but it really adds just a whole another level of I guess statistical complexity, real-world complexity, recruitment complexity, when you have a drug like this available in the market. 

 We have people on acetylcholinesterase inhibitors and memantine who are in trials that we know has a potential to affect to confound the data to some extent. You're right, it may be that it becomes an acceptable treatment. I'm seeing over time; I would say across the board for not just Alzheimer's studies but other clinical trials, are a greater and greater allowance for other modalities being used simultaneously. Obviously, someone can't be on more than 1 clinical trial at the same time but I think realistically, your point is probably going to become more the reality that either the studies allow these other treatments or they're really going to have a hard time enrolling. 

You also point out how important it is in addition to immunotherapy to look at these other modalities and other ways to try to get at this disease. As much as we know that the data, that the FDA based approval on and this aducanumab. What we're imagining we'll see with other immunotherapies is that it can rid the brain of amyloid, that there's the potential to slow to the disease course down. We clearly need more than that, we need better than that, and we don't want to compromise studies that are looking at other modalities and other ways to get at this disease. That's critically important.

Impact of the approval of aducanumab on the treatment landscape and other drugs in development for the treatment of Alzheimer disease. 

Impact of the Approval of Aducanumab on the Treatment Landscape in Alzheimer Disease 

I have a very unique practice, as you know. In the Alzheimer's prevention clinic, we only see people in the pre-dementia phase, so we see preclinical Alzheimer's patients that we've identified as having amyloid, but no symptoms or minimal symptoms that are not even close to MCI [mild cognitive impairment]. We see people with MCI, no dementia. They can still go about their activities of daily living. We already have this very robustly well-characterized group of people, very unique, though not very common. The question that I have is how do you identify the appropriate patient? How do you in clinical practice figure out who should go on aducanumab because the label is so broad? The treatment of Alzheimer's disease to me, if I'm looking at the definition of Alzheimer's, I include stages 1, 2, and 3, but the research data only really looked at people with MCI and early Alzheimer's disease in terms of their mini-mental, or in terms of their functioning.

The other part about how I look at who is the appropriate patient, it's not just about the efficacy part and which patient group should this drug be used to promote efficacy, which is, I guess, cognitive maintenance, or cognitive improvements, or reduction of amyloid? What is the definition of efficacy? That's complicated. Who is the appropriate patient from a safety perspective? In the Alzheimer's prevention clinic, we're already doing cognitive tests every 6 months. Well, that's helpful because we can understand trajectory. In the Alzheimer's prevention clinic, we're doing APOE [Apolipoprotein E] on everybody because the APOE4 variant increases risk a little bit, not good for diagnosis necessarily, but we use it to help personalize care, it is complex, a little controversial, but we use the APOE4 variant and it's helpful for us. I know that when a person with the APOE4 variant, actually, when they have 2 of them, they may be at higher risk for ARIA [amyloid-related imaging abnormalities], for vasogenic edema, for bleeding. They need to be more cautious with the dosing. Maybe we need to have a different titration schedule? We have a label that says treatment of Alzheimer's disease. We have a label that says do an MRI [magnetic resonance imaging] at 7 months and 12 months. Well, what if a person has 2-week 4s versus E33? We have a label that is so broad. I guess this is again, a lot to talk about, but what is the appropriate patient from an efficacy and a safety perspective based on the data and based on your feelings?  

 Well, to start with the efficacy front, the work you've done has really been pioneering in terms of looking at prevention. We know we need to start early and identify those individuals. Ideally, those are the individuals who we treat with this, because going back to my analogy before about the fire in the house, you want to put it out before there's a lot of damage. The brain does not repair itself as readily and as quickly as other parts of your body, we just know that. Theoretically, the earlier we catch in a rid the brain of amyloid and tau, we would imagine, now this is not based on the data we have yet, but we would imagine and want to get immersion data showing that that will actually push off the emergence of this disease. It will really slow it down, but yet, we still have to establish that. On the 1 hand, those theoretically are the ideal patients. We need more data to really support that. Years before they get symptoms, that's when we should be using this, but we haven't really identified them or diagnosed them formally as Alzheimer's disease. You've identified the key challenge. Most of the calls I'm getting are from individuals or loved ones of individuals who have moderate to severe disease because they're willing to do anything, even if this is a Hail Mary and somehow would slow it down, and yet we know that they will not be appropriate because there is no data showing it's going to have an impact at that point. The efficacy thing I think will be straightened out over time. I think it will be a combination of clinicians and working with the payers and the insurance carriers to determine what's even to be covered in the first place. I am concerned about access to diverse communities because I think that there's going to be a greater challenge there. The other thing is that centers like you, centers like me, we're not-for-profit site. In terms of being able to give these treatments, sometimes it's more challenging and there's more barriers. 

The infusion sites in the community that we have to partner with, there's just a lot to be worked out. Safety is also important. On the 1 hand, I can tell you from being an investigator for every major immunotherapy trial over time, that we definitely see ARIA, whether it's vasogenic edema, or whether it's these microhemorrhages. However, most of the time it's asymptomatic. When it's symptomatic, it tends to be pretty mild. That's the good news about this. I think some of the accounts I've been reading tend to describe it a little more severe than it typically is, but usually, if we catch it, it's usually earlier than 7 months in some individuals. I have a question about waiting that long, and what if someone doesn't want to get an MRI, or what if someone can't get an MRI for some reason? What about individuals who because of a pacemaker or some metal in their body, they have early Alzheimer's disease, but you can't do an MRI? They're now ineligible for this, what do you do? Those safety issues also need to be clarified. I think what you're pointing out very clearly here is that in this first week amidst a lot of the hoopla and a lot of hope, there's so many questions and so many issues and concerns being raised that we really have to take our time to address these before rushing into wholesale treatment of individuals with this new agent.  

 I agree. In night 1, first night from 7:45 p.m. to at least 10 p.m., I was getting back to patients. I treat a lot of MCI patients. I have a lot of pre-clinical Alzheimer's patients. The patients I was calling back on that Monday night, every single 1, was invariably moderate to severe disease. Those are the patients that were calling, those patients that were emailing. “What can we do? I will rent an apartment in New York because we can't travel back and forth. If this is going to be it, we'll get a studio. We'll do whatever it takes.” You're exactly right. The people that are most interested at this exact moment, in those days, the sooner week, days, and weeks soon after, will be people that haven't really been shown to be effective that where the drug hasn't been tested and shown to be effective.  

 The other side of the concern of mine because there are people who, for good reason are desperate. It's been almost 20 years since any approved treatment and they're willing to pay money and do what they need to do. You and I both see that they do things sometimes that have no scientific validity and they're exploited at times and they end up spending a lot of money on treatments that there's no evidence for. I'm concerned, in this case, if there will be areas in which people are just going to pay just to get it done even in those stages where it's not supported.  

 The other side of the coin which I think will defer for conversation at this time, maybe we can talk about this offline but pre-clinical Alzheimer's disease never been studied. We don't really have data. We have the A4 study using solanezumab in a preclinical Alzheimer's population. We have other studies the AHEAD 3-45 study which is going to be using lecanemab or BAN2401. It was the old name. Looking at more of the preclinical population, actually, they even defined it as early preclinical and I think later pre-clinical, something like that. Is this going to be used for people with pre-clinical Alzheimer's disease? When do you pull the trigger? That's off-label, or is it off-label? Because, it says the treatment of Alzheimer's and pre-clinical Alzheimer's diseases invariably Alzheimer's disease, or is it?  

That's a key point. What's on-label and what's off-label because we know how the diagnosis. It varied over time and we make clinical diagnoses without biomarkers all the time so does that count? There are no biomarker specifications.  

It's going to be an interesting several weeks and an interesting several months, I think for sure. 

The challenges of identifying the appropriate patient, earlier in the disease course, for treatment with aducanumab for Alzheimer disease.  

Identifying the Appropriate Patient for Treatment with Aducanumab in Alzheimer Disease 

 So much to talk about, as you mentioned earlier, the EMBARK study. The EMBARK study is a phase 3b open-label single-arm study, safety study also, to look at not just safety, but also efficacy of Aducanumab and it's going to be looking at people for 2 years, maybe it's 24 months, to understand what is truly the long-term efficacy and safety. The other part about this next phase of real-world clinical research in our clinical practices, you and I, and hundreds of other, thousands, who knows how many physicians are going to be prescribing this drug at some point, and the real-world impact kind of like the phase 4 outcomes of how aducanumab works and what the safety is. This is a very unique situation because we're going to be collecting data and the FDA said that the approval is contingent on collection of further data and clinician-researchers like us. Clinicians are going to at some point have to report these real-world outcomes and study them in a rigorous way. How do you think a physician should talk about this with a patient? You have an FDA approval, but you also have the need to continue to study whether or not it's effective and safe. How do you talk about that with a patient? 

This is a big challenge. It's important that the EMBARK study continues because we need to continue to gather data on individuals on aducanumab and it is open-label. These are individuals who've been on it before, and so we'll see over time whether – I think the FDA has given signal that this data is going to be really clear. It's going to be clear in terms of helping to determine to some extent the fate of aducanumab, but the problem is, once you've led the horse out of the barn, can you really put it back? Can you imagine if the data from EMBARK is not as positive as the other data a year or 2 years from now, and already hundreds, if not thousands of people are on the treatment? What will you do? I think that's going to be a challenge. The other issue is, how are we going to identify these individuals? You and I know that with the diagnostic process, you really have to take it seriously. These are not just shooting from the hip diagnoses.

My concern is that there's going to be individuals who are going to come into their primary care doctors and other individuals who this is not what they do every day and there's going to be a lot of pressure to just put them on this treatment. Will the diagnostic process be as careful? If it's not outlined now, if it's not in the package label, what will it entail? I think there's a lot ahead that we really need to determine. I'm also concerned about the impact of this on other research studies. At our MIND Institute center at Miami Jewish Health, we conduct all the major Alzheimer's disease trials, and already I'm hearing from subjects who say, “Well, why would I go into a placebo-controlled trial if I can get the real thing?” At the same time, we know, and I know as an investigator that, in general with these studies, if you're not rigorously looking at the metrics of it, it can be hard to really tell what's going on with someone. If we're doing this treatment in the real world, and it's approved, and we're not really collecting any data on it, how do we know we're slowing it down? It would be nice if somehow, we can build into the real-world use of this, some set of metrics that we can follow over time, and this data can help over time. I think that's really important. I think that will help address some of the concerns that I'm hearing from a lot of clinicians out there on this. 

The importance of the ongoing EMBARK phase III clinical trial and the collection of real-world data on the use of aducanumab is discussed. 

EMBARK Phase III Clinical Trial of Aducanumab in Alzheimer Disease 

Hello, and thank you for joining this NeurologyLive Peers and Perspectives presentation, entitled “Advances in the Treatment of Alzheimer's Disease”. Today, we're going to be discussing the recent FDA approval of aducanumab, and the current status of drugs in development for the treatment of Alzheimer's. My name is Dr Richard Isaacson. I'm the director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine in New York-Presbyterian in New York City. I'm also an assistant dean of faculty development at Weill Cornell. Today, I'm very privileged and looking forward to this chat, Marc. I'm here with Dr Marc Agronin. He's the senior vice president of behavioral health and chief medical officer for the MIND [Medical Investigation of Neurodevelopmental Disorders] Institute at Miami Jewish Health in Miami, Florida. Thanks so much for joining. Let's begin. Dr Agronin, we've been on this road together for over 15 years or so. 

When I was back in Miami, you were the 1 I referred my patients to for all the clinical trials, and for the amyloid studies. We've had patients in these amyloid studies for 15 years. I still remember the first person infused in the phase 2 bapineuzumab. What a week it's been with the approval of aducanumab. Marc, I don't even know where to begin because it's such a milestone in our field, but when you heard aducanumab was approved, what was the very first thing to go through your mind?  

Well, first of all, Richard, thank you for the invitation to be here. You're right, we've worked together a long time with many mutual patients. It's been a long journey. I think my initial reaction this week was 1 of hope, that we are making some moves in terms of being able to offer disease modification to patients even though we know that there's a lot of questions and some controversy over this. I think as you mentioned before, we've been on a long journey here. Reflecting back 15 years ago, we knew back then that the scope of Alzheimer's disease, but we really struggled to accurately diagnose it. We knew that immunotherapy played a role with these transgenic mice that are really seemed – we could see a cleared amyloid from their brains and they seemed to get better. We were on the verge of these new immunotherapy trials in humans. There was a lot of excitement. Now, 15 years later, we have something on the market. I think we're excited, we're hopeful, but there's a lot to talk about and a lot of issues we still need to address here. 

 I think the same exact thing from my end. I didn't know, I couldn't make predictions. I just didn't know what was going to happen. I think most people didn't know. I think some people felt 1 way. Other people felt another way. When it comes to the quality of scientific data, having done many investigator-initiated trials where I've created the trial, I've written the IRB [institutional review board], I've written the study protocol, I've gone for months or years sometimes with statisticians, I understand how hard it is to get quality research done. I have empathy. Even when you have billions of dollars or millions of dollars, whatever it is to invest in a clinical research pipeline and clinical trials, it is hard to get studies done. How valid is the data? What's the data quality? We can argue about that a lot, and we can talk about the studies and what one study showed them, what the other did and what the statistical analysis and future. We can talk about that, but I feel like we're on a different side now. We now have a drug that's approved for patients. I feel like we should probably focus more on what does this mean? The drug was approved, and the FDA labeling and the package insert for the treatment of Alzheimer's disease, full stop. The drug was approved based on reducing amyloid in the brain. Interesting.  

The FDA has done something a little bit different this time because especially when an initial label has started to come out, we all realize that in part, this is really focused on amyloid reduction and to some extent over time, it's going to stand or fall on the integrity of the amyloid hypothesis for Alzheimer's disease. We know from the very first study that Eloise Alzheimer did on his patient, where he looked at brain tissue. We know that amyloid and tau, these plaques and tangles are the hallmarks of this disease. The question all along has been, “Are they the only hallmarks?” If you get rid of one or both of them, what does that do for the disease?

We've seen clearly through research that these medications can reduce amyloid burden. We know that. The real question is what does that mean? I sometimes use the analogy of if your house is on fire and you put out the fire, maybe that's going to stop any further problems, but you've got a lot of damage there. We know that's the case with brains, with Alzheimer's disease, and for that matter, for other forms of neurocognitive disorders. By the time they walk into their office, there's so much damage in the brain. The question is, “What can we possibly do to mitigate that?” It's a dilemma, and we're still going to see over time with the ongoing EMBARK trial, which is still looking at individuals on aducanumab and gathering data. That's going to really help tell the full story over the coming years. 

This is the first drug approved in almost 20 years. I think it's 18 years, or so. When you look at the failures, you look at the minimal success, this is the first time I've actually gone back and read a package insert in a while. I remember package inserts as being quite long. I remember they would unroll them and read every word in small print. This one had a PDF, so I could make it larger. I stopped several times during reading it because I didn't know what the package insert would say. Would there be a requirement for an amyloid test to prove that the person has amyloid if you're going to be given an amyloid drug? That's 1 thing. Well, there wasn't that written in the package insert, so now is that the responsibility of the physician? That's 1 thing I wanted to chat with you about. Number 2, it's for the treatment of Alzheimer's disease. When I think about the term Alzheimer's disease, I think of stage 1, 2, and 3. Stage 1, preclinical, pre-symptomatic Alzheimer's, where there's amyloid in the brain, but no symptoms yet. Forty-six million Americans are estimated to have preclinical Alzheimer's. I call that Alzheimer's. Then there's MCI due to Alzheimer's, mild cognitive impairment due to Alzheimer's disease. They have amyloid in the brain. They have mild symptoms, but they don't have dementia. They can still take care of themselves. Then I also think about Alzheimer's disease as mild, moderate, and severe Alzheimer's disease, where the person can no longer take care of themselves. When I was in med school, that's what I learned Alzheimer's disease was- dementia, if they had it, that's when the disease started. We now know Alzheimer's pathology begins in the brain decades, 20 to 30, or probably more even decades before symptoms began. There is a lot to talk about Marc, but when you think about these 2 big elephants in the room, maybe, the FDA has allowed, or given the physician the free roam or wherewithal to figure this out, to figure out which patients, which stage, do we need a marker? Do we not? What are your thoughts about the amyloid biomarker aspect and what are your thoughts about what truly is the treatment of Alzheimer's disease? What are the stages when to use it? What do you think?  

You've really described the major shift that we've seen in the past decade, and that is going from making a good guess on whether someone has Alzheimer's disease to now seeing evidence. I refer to this imaging modality as basically virtual brain biopsies because we get a window into, “Is there amyloid, is there tau in the brain?” On the one hand, it's brought us clarity. It's allowed us to study treatments and individuals who actually have what we're trying to target. They have amyloid in the brain, or now with newer studies, they have tau in their brain. That's been an important change. It's also, as you said, allowed us to recognize that this disease doesn't begin when someone walks in our office. It's been going on a long time. 

On the other hand, it's proved vexing, because we're seeing individuals who are minimally or not symptomatic at all, and they have amyloid in their brain. What does that mean? And now tau, what does that mean? We can't predict the course. As you and I both know, as we follow people over virtual, literally for the rest of their lives, we've seen many different courses. We really appreciate the heterogeneity of this disorder. I have individuals who if you do nothing and we know they have amyloid, they tend to do pretty well and drifts slowly over the years, and we see other people who really progress very quickly. We see the same thing in these clinical trials. I would add on top of this, what makes it more confusing, is as people come in who in past years, I would say, absolutely, this is Alzheimer's disease. They fit the clinical picture. They fit the progression, but they have no amyloid in their brain, or they have no tau in their brain. What do we diagnose them with? We can say this is a major neurocognitive disorder, but that doesn't bring much clarity. As much as this new era of biomarkers has really helped us to understand better what's going on in someone's brain has also brought so many more questions and areas that need to be clarified over time. 

Now we bring aducanumab into this. The question is, and unfortunately, at least at this point, the label is not helpful, who will qualify for this? I think this is a dilemma because as clinicians, you and I can talk about how we make a diagnosis, but we both know that a lot of this is going to be the hands of the payers. They may say, “You have to have a spinal tap. You have to have amyloid scan.” But will they pay for it? There's a lot yet to be revealed in the coming weeks and months before we really have a sense for who will be able to get this treatment who will have access to it. That lies ahead. 

Expert neurologists, Richard S. Isaacson, MD, and Marc E. Agronin, MD, describe the journey to the FDA approval of aducanumab for the treatment of Alzheimer disease and what this means for clinicians. 

Marc E. Agronin, MD

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